Project Summary/Abstract This project is aimed at developing a novel type of nanoparticle formulation for targeted chemo-phototherapeutic destruction of tumors. Specifically, these nanoparticles are hybrid structures composed of erythrocyte-derived vesicles doped with two FDA-approved agents: the near infrared (NIR) chromophore, indocyanine green (ICG), and chemotherapeutic drug, doxorubicin hydrochloride (DOX). Furthermore, the surface of the nanoparticles is functionalized with the FDA-approved humanized monoclonal antibodies, Herceptin, for molecular targeting of the human epidermal growth factor receptor-2 (HER-2), whose over-expression is associated with the carcinogenesis of various solid tumors. We refer to these nanoparticles as ICG & DOX loaded NIR erythrocyte-derived transducers (ID-NETs). Upon activation by an appropriate NIR wavelength, they can transduce the absorbed light energy to generate heat for photothermal destruction of tumor, and also trigger the release of DOX into the tumor site. We hypothesize that the local delivery of ID-NETs into tumors along with combined dual photothermal-chemotherapeutic effects will lower the optical and drug dosages necessary for destruction of tumors than the corresponding dosages associated with the single modality treatment. This approach should ultimately lead to enhanced therapeutic outcomes, and reduce side effects that may otherwise result from the systemic delivery of chemotherapeutic agents, particularly at higher dosages. Our long-term goal is to commercialize ID-NETs as an agent for chemo- phototherapeutic destruction of tumors. There are no prior reports of an erythrocyte-derived nanoparticle formulation for targeted chemo-phototherapeutic destruction of tumors. Therefore, this proposal presents a highly innovative technology in treating tumors, and the first step in investigating the potential of these nanoparticles for future clinical translation. Our specific aims (SAs) during this Phase I project are to: (1) fabricate, characterize and optimize the formulation of ID-NETs for maximum ICG and DOX loading (SA1); (2) investigate the effects of pH and laser power densities on the release kinetics of ICG and DOX from a series of ID-NETs formulations (SA2); (3) validate the effectiveness of Herceptin- functionalized ID-NETs for targeted in vitro chemo-photothermal destruction of cancer cells (SA3); (4) Investigate the utility of Herceptin-functionalized ID-NETs in mediating chemo-photothermal therapy of tumors in mice (SA4). Upon completion of the proposed Phase I studies, we will identify the optimum formulation of Herceptin- functionalized ID-NETs for maximum ICG and DOX loading, and demonstrate the feasibility for targeted chemo- photothermal therapy of tumors. Our activities during Phase II will include the development of fabrication standardization procedures and full commercialization plans. Given the existing FDA-approved status of ICG, DOX, Herceptin, and prior clinical studies with erythrocytes-based delivery systems, ID-NETs present a promising candidate for clinical translation. This Phase I application is the first step towards these endeavors.